This 5-year K08 training program is designed to advance the career of Renuka Nayak, M.D., Ph.D., with the goal of preparing her for an independent research career as an academic physician-scientist. This multidisciplinary proposal interrogates the role of the human gut microbiome in the treatment of rheumatoid arthritis (RA) with methotrexate (MTX). At the conclusion of the award, Dr. Nayak will be an independent investigator leading a multidisciplinary research lab that will make substantial contributions to the understanding of the role of the gut microbiome in the personalized treatment of rheumatic diseases. Dr. Nayak will gain this expertise through the combined guidance of: her primary mentor, Peter Turnbaugh, Ph.D., a leader in microbiome studies in nutrition and pharmacology; Katie Pollard, Ph.D., a world-renowned statistician with expertise in large scale genomic and microbiome studies; Lindsey Criswell, M.D., an international leader in genomic studies in patients with autoimmune disease; and Mary Nakamura, M.D., a world-recognized leader in bone biology and bone immunology. Dr. Nayak and her mentors have developed a formal training plan with didactics, seminars, workshops, and experimental research that will propel her towards her career goals. The extensive resources at the University of California, San Francisco, an entirely biomedical campus with world experts and physician-scientists, as well as the deep commitment and support of her Department and Division will facilitate Dr. Nayak's pathway to independence and her long-term goals to advance the care of rheumatology patients through personalized medicine. RA is an inflammatory arthritis resulting in irreversible damage unless effective therapy is provided quickly. Oral MTX is first-line therapy for RA, but is ineffective in 50-70% of patients; clinicians currently employ a ?trial and error? approach to treatment. While many have studied whether genetics or environmental factors predict response, none have examined the role of the gut microbiome. Dr. Nayak's research has demonstrated that human gut bacteria metabolize MTX, and that fecal microbiomes from healthy individuals vary in their ability to metabolize MTX. Additionally, work from her collaborators suggests that the baseline, pre-treatment microbiome is associated with MTX response in RA patients. These observations motivate Dr. Nayak to test the hypothesis that gut bacterial metabolism of MTX interferes with RA treatment. She will investigate the following independent and complementary aims: (1) define a mechanism for the role of the baseline microbiome in clinical MTX response, (2) elucidate the effects of MTX treatment on bacterial drug metabolism, and (3) establish an in vivo model to test the relevance of MTX metabolism by the microbiome. The proposed studies will provide insight into the mechanisms by which the microbiome affects the treatment of rheumatologic disease. Defining these mechanisms will advance our knowledge of the role of the microbiome in precision medicine.